Electronic breath actuated in-line droplet delivery device with small volume ampoule and methods of use

ABSTRACT

A droplet delivery device with a small volume drug ampoule and related methods for delivering precise and repeatable dosages to a subject for pulmonary use is disclosed. The droplet delivery device is configured to facilitate the ejection of small, e.g., single use, volumes of a therapeutic agent. The droplet delivery device includes a housing, a mouthpiece, a small volume drug ampoule, an ejector mechanism, and at least one differential pressure sensor. The delivery device is automatically breath actuated by the user when the differential pressure sensor senses a predetermined pressure change within housing. The droplet delivery device is then actuated to generate a plume of droplets having an average ejected particle diameter within the respirable size range, e.g, less than about 5-6 μm, so as to target the pulmonary system of the user. The small volume drug ampoule may include a reservoir which comprises an internal flexible membrane separating two internal volumes, a first background pressure fluid volume and a second drug volume.

RELATED APPLICATIONS

The present application claims benefit under 35 U.S.C. § 119 of U.S.Provisional Patent Application No. 62/583,310, filed Nov. 8, 2017,entitled “ELECTRONIC BREATH ACTUATED IN-LINE DROPLET DELIVERY DEVICEWITH SINGLE USE AMPOULE AND METHODS OF USE”, the contents of which areeach herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

This disclosure relates to droplet delivery devices and morespecifically to droplet delivery devices for the delivery of fluids tothe pulmonary system.

BACKGROUND OF THE INVENTION

The use of aerosol generating devices for the treatment of a variety ofrespiratory diseases is an area of large interest. Inhalation providesfor the delivery of aerosolized drugs to treat asthma, COPD andsite-specific conditions, with reduced systemic adverse effects. A majorchallenge is providing a device that delivers an accurate, consistent,and verifiable dose, with a droplet size that is suitable for successfuldelivery of medication to the targeted lung passageways.

Dose verification, delivery and inhalation of the correct dose atprescribed times is important. Getting patients to use inhalerscorrectly is also a major problem. A need exists to insure that patientscorrectly use inhalers and that they administer the proper dose atprescribed times. Problems emerge when patients misuse or incorrectlyadminister a dose of their medication. Unexpected consequences occurwhen the patient stops taking medications, owing to not feeling anybenefit, or when not seeing expected benefits or overuse the medicationand increase the risk of over dosage. Physicians also face the problemof how to interpret and diagnose the prescribed treatment when thetherapeutic result is not obtained.

Currently most inhaler systems such as metered dose inhalers (MDI) andpressurized metered dose inhalers (p-MDI) or pneumatic andultrasonic-driven devices generally produce droplets with highvelocities and a wide range of droplet sizes including large dropletthat have high momentum and kinetic energy. Droplets and aerosols withsuch high momentum do not reach the distal lung or lower pulmonarypassageways, but rather are deposited in the mouth and throat. As aresult, larger total drug doses are required to achieve the desireddeposition in targeted pulmonary areas. These large doses increase theprobability of unwanted side effects.

Aerosol plumes generated from current aerosol delivery systems, as aresult of their high ejection velocities and the rapid expansion of thedrug carrying propellant, may lead to localized cooling and subsequentcondensation, deposition and crystallization of drug onto the devicesurfaces. Blockage of device surfaces by deposited drug residue is alsoproblematic.

This phenomenon of surface condensation is also a challenge for existingvibrating mesh or aperture plate nebulizers that are available on themarket. In these systems, in order to prevent a buildup of drug ontomesh aperture surfaces, manufacturers require repeated washing andcleaning, as well as disinfection after a single use in order to preventpossible microbiological contamination. Other challenges includedelivery of viscous drugs and suspensions that can clog the apertures orpores and lead to inefficiency or inaccurate drug delivery to patientsor render the device inoperable. Also, the use of detergents or othercleaning or sterilizing fluids may damage the ejector mechanism or otherparts of the nebulizer and lead to uncertainty as to the ability of thedevice to deliver a correct dose to the patient or state of performanceof the device.

Accordingly, there is a need for a droplet delivery device that deliversdroplets of a suitable size range, avoids surface fluid deposition andblockage of apertures, with a dose that is verifiable, and providesfeedback regarding correct and consistent usage of the device topatients and professionals such as physicians, pharmacists ortherapists.

SUMMARY OF THE INVENTION

In one aspect, the disclosure relates to a breath actuated dropletdelivery device for delivering a small volume of fluid as an ejectedstream of droplets to the pulmonary system of a subject. In certainembodiments, the droplet delivery device is configured to facilitate theejection of small, e.g., single use, volumes of a therapeutic agent.

In certain embodiments, the droplet delivery device may include: ahousing; a mouthpiece positioned at the airflow exit side of thehousing; a small volume drug ampoule disposed in or in fluidcommunication with the housing including a drug reservoir for receivinga small volume of fluid; an ejector mechanism in fluid communicationwith the reservoir, the ejector mechanism comprising a piezoelectricactuator and an aperture plate, the aperture plate having a plurality ofopenings formed through its thickness and the piezoelectric actuatoroperable to oscillate the aperture plate at a frequency to therebygenerate an ejected stream of droplets, at least one differentialpressure sensor positioned within the housing; the at least onedifferential pressure sensor configured to activate the ejectormechanism upon sensing a pre-determined pressure change within themouthpiece to thereby generate an ejected stream of droplets; theejector mechanism configured to generate the ejected stream of dropletswherein at least about 50% of the droplets have an average ejecteddroplet diameter of less than about 6 microns, such that at least about50% of the mass of the ejected stream of droplets is delivered in arespirable range to the pulmonary system of a subject during use. Incertain embodiments, the small volume drug ampoule may include areservoir which comprises an internal flexible membrane separating twointernal volumes, a first background pressure fluid volume and a seconddrug volume.

In some aspects, the droplet delivery device further includes an airinlet flow element positioned in the airflow at the airflow entrance ofthe device and configured to facilitate non-turbulent (i.e., laminarand/or transitional) airflow across the exit side of aperture plate andto provide sufficient airflow to ensure that the ejected stream ofdroplets flows through the droplet delivery device during use. In someembodiments, the air inlet flow element may be positioned within themouthpiece.

In certain embodiments, the housing and ejector mechanism are orientedsuch that the exit side of the aperture plate is perpendicular to thedirection of airflow and the stream of droplets is ejected in parallelto the direction of airflow. In other embodiments, the housing andejector mechanism are oriented such that the exit side of the apertureplate is parallel to the direction of airflow and the stream of dropletsis ejected substantially perpendicularly to the direction of airflowsuch that the ejected stream of droplets is directed through the housingat an approximate 90 degree change of trajectory prior to expulsion fromthe housing.

In certain aspects, the droplet delivery device further includes asurface tension plate between the aperture plate and the reservoir,wherein the surface tension plate is configured to increase contactbetween the volume of fluid and the aperture plate. In other aspects,the ejector mechanism and the surface tension plate are configured inparallel orientation. In yet other aspects, the surface tension plate islocated within 2 mm of the aperture plate so as to create sufficienthydrostatic force to provide capillary flow between the surface tensionplate and the aperture plate.

In yet other aspects, the aperture plate of the droplet delivery devicecomprises a domed shape. In other aspects, the aperture plate may beformed of a metal, e.g., stainless steel, nickel, cobalt, titanium,iridium, platinum, or palladium or alloys thereof. Alternatively, theplate can be formed of suitable material, including other metals orpolymers, In other aspects. In certain embodiments, the aperture plateis comprised of, e.g., poly ether ether ketone (PEEK), polyimide,polyetherimide, polyvinylidine fluoride (PVDF), ultra-high molecularweight polyethylene (UHMWPE), nickel, nickel-cobalt, palladium,nickel-palladium, platinum, or other suitable metal alloys, andcombinations thereof. In other aspects, one or more of the plurality ofopenings of the aperture plate have different cross-sectional shapes ordiameters to thereby provide ejected droplets having different averageejected droplet diameters.

In yet other aspects, the reservoir of the droplet delivery device isremovably coupled with the housing. In other aspects, the reservoir ofthe droplet delivery device is coupled to the ejector mechanism to forma combination reservoir/ejector mechanism module, and the combinationreservoir/ejector mechanism module is removably coupled with thehousing.

In other aspects, the droplet delivery device may further include awireless communication module. In some aspects, the wirelesscommunication module is a Bluetooth transmitter.

In yet other aspects, the droplet delivery device may further includeone or more sensors selected from an infer-red transmitter, aphotodetector, an additional pressure sensor, and combinations thereof.

In one aspect, the disclosure relates to a method for generating anddelivering a fluid as an ejected stream of droplets to the pulmonarysystem of a subject in a respirable range. The method may comprise: (a)generating an ejected stream of droplets via a breath actuated dropletdelivery device of the disclosure, wherein at least about 50% of theejected stream of droplets have an average ejected droplet diameter ofless than about 6 μm; and (b) delivering the ejected stream of dropletsto the pulmonary system of the subject such that at least about 50% ofthe mass of the ejected stream of droplets is delivered in a respirablerange to the pulmonary system of a subject during use.

In another aspect, this disclosure relates to a method for delivering atherapeutic agent as an ejected stream of droplets in a respirable rangeto the pulmonary system of a subject for the treatment of a pulmonarydisease, disorder or condition. The method may comprise: (a) generatingan ejected stream of droplets via a breath actuated droplet deliverydevice of the disclosure, wherein at least about 50% of the ejectedstream of droplets have an average ejected droplet diameter of less thanabout 6 μm; and (b) delivering the ejected stream of droplets to thepulmonary system of the subject such that at least about 50% of the massof the ejected stream of droplets is delivered in a respirable range tothe pulmonary system of a subject during use to thereby treat thepulmonary disease, disorder or condition.

In certain embodiments, the pulmonary disease, disorder or condition isselected from asthma, chronic obstructive pulmonary diseases (COPD)cystic fibrosis (CF), tuberculosis, chronic bronchitis, and pneumonia.In other embodiments, the pulmonary disease is lung cancer. In furtheraspects, the therapeutic agent is a COPD medication, an asthmamedication, or an antibiotic. The therapeutic agent may be selected fromalbuterol sulfate, ipratropium bromide, tobramycin, fluticasonepropionate, fluticasone furoate, tiotropium, glycopyrrolate, olodaterol,salmeterol, umeclidinium, and combinations thereof. In yet otheraspects, the therapeutic agent may be delivered to the pulmonary systemof the subject at a reduced dosage, as compared to standard propellantbased inhaler dosages.

In yet another aspect, the disclosure relates to a method for thesystemic delivery of a therapeutic agent as an ejected stream ofdroplets in a respirable range to the pulmonary system of a subject forthe treatment of a disease, disorder or condition. The method maycomprise: (a) generating an ejected stream of droplets via apiezoelectric actuated droplet delivery device, wherein at least about50% of the ejected stream of droplets have an average ejected dropletdiameter of less than about 6 μm; and (b) delivering the ejected streamof droplets to the pulmonary system of the subject such that at leastabout 50% of the mass of the ejected stream of droplets is delivered ina respirable range to the pulmonary system of a subject during use tothereby systemically delivery the therapeutic agent to the subject totreat the disease, disorder or condition.

In certain embodiments, the disease, disorder or condition is selectedfrom diabetes mellitus, rheumatoid arthritis, plaque psoriasis, Crohn'sdisease, hormone replacement therapy, neutropenia, nausea, andinfluenza.

In further aspects, the therapeutic agent is a therapeutic peptide,protein, antibody, or other bioengineered molecule. In yet furtheraspects, the therapeutic agent is selected from growth factors, insulin,vaccines, antibodies, Fc-fusion protein, hormones, enzymes, genetherapies and RNAi cell therapies, antibody-drug conjugates, cytokines,anti-infective agents, polynucleotides, oligonucleotides, or anycombination thereof. In other aspects, the therapeutic agent isdelivered to the pulmonary system of the subject at a reduced dosage, ascompared to oral or intravenous dosages.

While multiple embodiments are disclosed, still other embodiments of thepresent disclosure will become apparent to those skilled in the art fromthe following detailed description, which shows and describesillustrative embodiments of the disclosure. As will be realized, theinvention is capable of modifications in various aspects, all withoutdeparting from the spirit and scope of the present disclosure.Accordingly, the detailed descriptions are to be regarded asillustrative in nature and not restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B illustrate perspective views of an exemplary in-line dropletdelivery device, in accordance with embodiments of the disclosure.

FIG. 2 is an exploded view of an in-line droplet delivery device of FIG.1A-1B, in accordance with embodiments of the disclosure.

FIG. 3A-1 is a partial perspective view of a base unit of an in-linedroplet delivery device of FIG. 1A-1B, in accordance with embodiments ofthe disclosure.

FIG. 3A-2 is an exploded view of an in-line droplet delivery device ofFIG. 1A-1B, in accordance with embodiments of the disclosure.

FIG. 3B-1 is a bottom perspective view of a drug delivery ampoule of anin-line droplet delivery device of FIG. 1A-1B, in accordance withembodiments of the disclosure.

FIG. 3B-2 is an exploded view of an in-line droplet delivery device ofFIG. 1A-1B, in accordance with embodiments of the disclosure.

FIGS. 3C-1, 3C-2, and 3C-3 are cross section perspective views of anin-line droplet delivery device of FIG. 1A-1B, in accordance withembodiments of the disclosure.

FIGS. 4A-4B illustrate perspective views of another exemplary in-linedroplet delivery device, in accordance with embodiments of thedisclosure.

FIG. 5 is an exploded view of an in-line droplet delivery device of FIG.4A-4B, in accordance with embodiments of the disclosure.

FIG. 6 is a cross section perspective view of an in-line dropletdelivery device of FIG. 4A-4B, in accordance with embodiments of thedisclosure.

FIG. 7 is a perspective view of an in-line droplet delivery device ofFIG. 4A-4B without the drug delivery ampoule inserted, in accordancewith embodiments of the disclosure.

FIGS. 8A-8B are perspective views of a drug delivery ampoule andmouthpiece cover, showing a front view (FIG. 8A) and back view (FIG.8B), in accordance with embodiments of the disclosure.

FIG. 9 is a cross-section of an exemplary small volume drug ampoule, inaccordance with an embodiment of the disclosure.

FIGS. 10A-10C show an alternative drug delivery ampoule, with FIG. 9Ashowing a perspective view, FIG. 9B showing a top exploded view, andFIG. 9C showing a bottom exploded view.

FIG. 11A is a partial cross section perspective view of an in-linedroplet delivery device of FIG. 1A-1B comprising a drug deliveryampoule, mouthpiece including an air inlet flow element, and mouthpiececover, in accordance with an embodiment of the disclosure.

FIG. 11B is a front view of an in-line droplet delivery device of FIG.1A-1B comprising a drug delivery ampoule and mouthpiece including an airinlet flow element, in accordance with an embodiment of the disclosure.

FIG. 11C is a exploded view of components of an in-line droplet deliverydevice of FIG. 1A-1B including a mouthpiece and internal housing, inaccordance with an embodiment of the disclosure.

FIG. 12A is a plot of the differential pressure as a function of flowrates through exemplary air inlet flow elements as a function of numberof holes, in accordance with an embodiment of the disclosure.

FIG. 12B is a plot of the differential pressure as a function of flowrates through exemplary air inlet flow elements as a function of screenhole size and number of holes set at a constant, 17 holes, in accordancewith an embodiment of the disclosure.

FIG. 13A shows an exemplary drug delivery ampoule with a mouthpieceinterfaced at the airflow exit side of the device, in accordance with anembodiment of the disclosure. FIG. 13B shows a front cross-section andFIG. 13C shows a side cross-section, with FIG. 13D showing the sameviews with exemplary dimensions.

FIG. 14A shows an alternative drug delivery ampoule with a mouthpieceinterfaced at the airflow exit side of the device, in accordance with anembodiment of the disclosure. FIG. 14B shows a front cross-section andFIG. 14C shows a side cross-section, with FIG. 14D showing the sameviews with exemplary dimensions.

FIG. 15A shows an alternative drug delivery ampoule with a mouthpieceinterfaced at the airflow exit side of the device, in accordance with anembodiment of the disclosure. FIG. 15B shows a front cross-section andFIG. 15C shows a side cross-section, with FIG. 15D showing the sameviews with exemplary dimensions.

FIG. 16A shows an exemplary drug delivery ampoule with a mouthpieceinterfaced at the airflow exit side of the device, in accordance with anembodiment of the disclosure. The mouthpiece includes two airflowentrances on the exterior sides of the mouthpiece, and two interiorbaffles with additional airflow entrances to provide resistance andmodeling of airflow. FIG. 16B shows a front cross-section and FIG. 16Cshows a side cross-section, with FIG. 16D showing the same views withexemplary dimensions.

FIG. 17A shows an exemplary drug delivery ampoule with a mouthpieceinterfaced at the airflow exit side of the device, in accordance with anembodiment of the disclosure. The mouthpiece includes two airflowentrances on the exterior sides of the mouthpiece, and two interiorbaffles with additional airflow entrances to provide resistance andmodeling of airflow. FIG. 17B shows a front cross-section and FIG. 17Cshows a side cross-section, with FIG. 17D showing the same views withexemplary dimensions.

FIG. 18A shows an exemplary drug delivery ampoule with a mouthpieceinterfaced at the airflow exit side of the device, in accordance with anembodiment of the disclosure. The mouthpiece includes two airflowentrances on the exterior sides of the mouthpiece, and a substantiallyconcentric baffle (two arcs that form a circle with the top and bottomof the mouthpiece) with two additional airflow entrances to provideresistance and modeling of airflow. FIG. 18B shows a front cross-sectionand FIG. 18C shows a side cross-section, with FIG. 18D showing the sameviews with exemplary dimensions.

FIG. 19A shows an exemplary drug delivery ampoule with a mouthpieceinterfaced at the airflow exit side of the device, in accordance with anembodiment of the disclosure. The mouthpiece includes two airflowentrances on the exterior sides of the mouthpiece, and a substantiallyconcentric baffle (two arcs that form a circle with the top and bottomof the mouthpiece) with four airflow entrances to provide resistance andmodeling of airflow. FIG. 19B shows a front cross-section and FIG. 19Cshows a side cross-section, with FIG. 19D showing the same views withexemplary dimensions.

FIG. 20A shows an exemplary drug delivery ampoule with a mouthpieceinterfaced at the airflow exit side of the device, in accordance with anembodiment of the disclosure. The mouthpiece includes two airflowentrances on the exterior sides of the mouthpiece, and a substantiallyconcentric baffle with two additional airflow entrances to provideresistance and modeling of airflow. In addition, the interior area ofthe mouthpiece between the concentric baffle and the wall of themouthpiece includes an array element positioned above the airflowentrances to provide additional resistance and modeling to airflow. Thearray element is positioned in a parallel arrangement with the directionof airflow. FIG. 20B shows a front cross-section and FIG. 20C shows aside cross-section, with FIG. 20D showing the same views with exemplarydimensions.

FIG. 21 is a plot of spray efficiency as a function of flow ratesthrough exemplary air inlet flow elements as a function of number andconfiguration of openings, baffles, etc., in accordance with anembodiment of the disclosure.

FIGS. 22A-22D illustrate exemplary aperture plate seal mechanisms, inaccordance with embodiments of the disclosure. FIG. 22A showing theampoule in end view, FIG. 22B and FIG. 22C showing the ampoule in sideview. FIG. 22D illustrates an alternative embodiment wherein themouthpiece cover includes an aperture plate plug.

DETAILED DESCRIPTION

Effective delivery of medication to the deep pulmonary regions of thelungs through the alveoli, has always posed a problem, especially tochildren and elderly, as well as to those with the diseased state, owingto their limited lung capacity and constriction of the breathingpassageways. The impact of constricted lung passageways limits deepinspiration and synchronization of the administered dose with theinspiration/expiration cycle. For optimum deposition in alveolarairways, droplets with aerodynamic diameters in the ranges of 1 to 5 μmare optimal, with droplets below about 4 μm shown to more effectivelyreach the alveolar region of the lungs, while larger droplets aboveabout 6 μm are deposited on the tongue or strike the throat and coat thebronchial passages. Smaller droplets, for example less than about 1 μmthat penetrate more deeply into the lungs have a tendency to be exhaled.

Certain aspects of the disclosure relate to an electronic, fully digitalplatform for delivery of inhaled therapeutics, described herein as anin-line droplet delivery device or soft mist inhaler (SMI) device with asmall volume drug ampoule. In some embodiments, the small volume ampouleis a single use ampoule. The device provides substantial improvementsover current inhaled delivery systems by improving dosing precision,dosing reliability, and delivery to the patient. In certain embodiments,the device of the disclosure includes fully integrated monitoringcapabilities designed to enhance compliance and ultimately reducedisease associated morbidity.

In certain aspects, the present disclosure relates to an in-line dropletdelivery device with a small volume drug ampoule for delivery a fluid asan ejected stream of droplets to the pulmonary system of a subject andrelated methods of delivering safe, suitable, and repeatable dosages tothe pulmonary system of a subject. The present disclosure also includesan in-line droplet delivery device with a small volume drug ampoule andsystem capable of delivering a defined volume of fluid in the form of anejected stream of droplets such that an adequate and repeatable highpercentage of the droplets are delivered into the desired locationwithin the airways, e.g., the alveolar airways of the subject duringuse.

The present disclosure provides an in-line droplet delivery device witha small volume drug ampoule for delivery of a fluid as an ejected streamof droplets to the pulmonary system of a subject, the device comprisinga housing, a mouthpiece, a small volume drug ampoule including a drugreservoir for receiving a small volume of fluid, and an ejectormechanism including a piezoelectric actuator and an aperture plate,wherein the ejector mechanism is configured to eject a stream ofdroplets having an average ejected droplet diameter of less than about 6microns, preferably less than about 5 microns.

In certain embodiments, the small volume drug ampoule may be configuredas a single use ampoule (e.g., disposable on a daily or on-use basis).Such embodiments are particularly useful with therapeutic agents thatare sensitive to storage conditions, e.g., sensitive to degradation,aggregation, conformational changes, contamination, etc. In this regard,the small volume drug ampoule allows for sterile storage of atherapeutic agent under appropriate conditions until the time of use,e.g., under a temperature controlled environment, as apowder-for-reconstitution, etc. By way of non-limiting example, thesmall volume drug ampoule of the disclosure is particular suitable foruse with therapeutic peptides, proteins, antibodies, and otherbioengineered molecules or biologics. However, the disclosure is not solimited, and the small volume drug ampoule may be used with anytherapeutic agent known in the art.

Without intending to be limited by theory, in certain aspects, the smallvolume drug ampoule of the disclosure may offer advantages over largervolume/multi-use ampoules in that, e.g., the limited duration of useminimizes evaporation of fluid in the reservoir, minimizes thepossibility of contamination of fluid in the reservoir and/or theejector surface, minimizes the duration of time of the ampoule is heldat non-controlled storage conditions, etc.

In certain embodiments, the small volume drug ampoule includes a drugreservoir for receiving a small volume of fluid, e.g., a volumeequivalent to 10 or fewer dosages, a volume equivalent to 5 or fewerdosages, a volume equivalent to 4 or fewer dosages, a volume equivalentto 3 or fewer dosages, a volume equivalent to 2 or fewer dosages, asingle dose volume. The small volume drug ampoule is configured tofacilitate the ejection of small, e.g., single use, volumes of atherapeutic agent. As will be described in further detail herein, thesmall volume drug ampoule may include a reservoir which comprises aninternal flexible membrane separating two internal volumes, a firstbackground pressure fluid volume and a second drug volume. In certainaspects, the membrane separates the two volumes such that the backgroundpressure fluid volume creates an area of fluid behind/above the drugvolume without allowing mixing or diluting of the therapeutic agent bythe background pressure fluid. The small volume drug ampoule may furthercomprise an air exchange vent or air space in the region of thebackground pressure fluid volume, configured to prevent or relieve thecreation of negative pressure during ejection of the drug fluid duringuse. As described herein, the air exchange vent may include asuperhydrophobic filter, optionally in combination with a spiral vaporbarrier, which provides for free exchange of air into and out of thereservoir.

As shown in further detail herein, the droplet delivery device isconfigured in an in-line orientation in that the housing, its internalcomponents, and various device components (e.g., the mouthpiece, airinlet flow element, etc.) are orientated in a substantially in-line orparallel configuration (e.g., along the airflow path) so as to form asmall, hand-held device. In certain embodiments, the housing and ejectormechanism are oriented such that the exit side of aperture plate isperpendicular to the direction of airflow and the stream of droplets isejected in parallel to the direction of airflow. In other embodiments,the housing and ejector mechanism are oriented such that the exit sideof aperture plate is parallel to the direction of airflow and the streamof droplets is ejected substantially perpendicularly to the direction ofairflow such that the ejected stream of droplets is directed through thehousing at an approximate 90 degree change of trajectory prior toexpulsion from the housing.

In specific embodiments, the ejector mechanism is electronically breathactivated by at least one differential pressure sensor located withinthe housing of the in-line droplet delivery device upon sensing apre-determined pressure change within the mouthpiece. In certainembodiments, such a pre-determined pressure change may be sensed duringan inspiration cycle by a user of the device, as will be explained infurther detail herein.

In some aspects, the droplet delivery device further includes an airinlet flow element positioned in the airflow at the airflow entrance ofthe housing and configured to facilitate non-turbulent (i.e., laminarand/or transitional) airflow across the exit side of aperture plate andto provide sufficient airflow to ensure that the ejected stream ofdroplets flows through the droplet delivery device during use. In someembodiments, the air inlet flow element may be positioned within themouthpiece As will be described in further detail herein, the air inletflow element may be positioned behind the exit side of the apertureplate along the direction of airflow, or in-line or in front of the exitside of the aperture plate along the direction of airflow. In certainembodiments, the air inlet flow element comprises one or more openingsformed there through and configured to increase or decrease internalpressure resistance within the droplet delivery device during use. Forinstance, the air inlet flow element comprises an array of one oropenings. In the embodiments, the air inlet flow element comprises oneor more baffles, e.g., wherein the one or more baffles comprise one ormore airflow openings.

In accordance with certain aspects of the disclosure, effectivedeposition into the lungs generally requires droplets less than about5-6 μm in diameter. Without intending to be limited by theory, todeliver fluid to the lungs a droplet delivery device must impart amomentum that is sufficiently high to permit ejection out of the device,but sufficiently low to prevent deposition on the tongue or in the backof the throat. Droplets below approximately 5-6 μm in diameter aretransported almost completely by motion of the airstream and entrainedair that carry them and not by their own momentum.

In certain aspects, the present disclosure includes and provides anejector mechanism configured to eject a stream of droplets within therespirable range of less than about 5-6 μm, preferably less than about 5μm. The ejector mechanism is comprised of an aperture plate that isdirectly or indirectly coupled to a piezoelectric actuator. In certainimplementations, the aperture plate may be coupled to an actuator platethat is coupled to the piezoelectric actuator. The aperture plategenerally includes a plurality of openings formed through its thicknessand the piezoelectric actuator directly or indirectly (e.g. via anactuator plate) oscillates the aperture plate, having fluid in contactwith one surface of the aperture plate, at a frequency and voltage togenerate a directed aerosol stream of droplets through the openings ofthe aperture plate into the lungs, as the patient inhales. In otherimplementations where the aperture plate is coupled to the actuatorplate, the actuator plate is oscillated by the piezoelectric oscillatorat a frequency and voltage to generate a directed aerosol stream orplume of aerosol droplets.

In certain aspects, the present disclosure relates to an in-line dropletdelivery device with a small volume drug ampoule for delivering a fluidas an ejected stream of droplets to the pulmonary system of a subject.The ejected stream of droplets includes, without limitation, dropletsformed from solutions, suspensions or emulsions which have viscositiesin a range capable of droplet formation using the ejector mechanism. Incertain aspects, the therapeutic agents may be delivered at a high doseconcentration and efficacy, as compared to alternative dosing routes andstandard inhalation technologies.

More specifically, the in-line droplet delivery device with a smallvolume drug ampoule may be used to deliver therapeutic agents as anejected stream of droplets to the pulmonary system of a subject for thelocal or systemic delivery of therapeutic agents including smallmolecules, therapeutic peptides, proteins, antibodies, and otherbioengineered molecules via the pulmonary system. In some embodiments,the in-line droplet delivery device may be used to locally orsystemically deliver therapeutic agents for the treatment or preventionof cancers, including pulmonary cancers. By way of non-limiting example,the in-line droplet delivery device may be used to systemically delivertherapeutic agents for the treatment or prevention of indicationsinducing, e.g., diabetes mellitus, rheumatoid arthritis, plaquepsoriasis, Crohn's disease, hormone replacement, neutropenia, nausea,influenza, etc.

By way of non-limiting example, therapeutic peptides, proteins,antibodies, and other bioengineered molecules include: growth factors,insulin, vaccines (Prevnor—Pneumonia, Gardasil—HPV), antibodies(Keytruda (pembrolizumab), Opdivo (nivolumab) Avastin (bevacizumab),Humira (adalimumab), Remicade (infliximab), Herceptin (trastuzumab)), FcFusion Proteins (Enbrel (etanercept), Orencia (abatacept)), hormones(Elonva—long acting FSH, Growth Hormone), enzymes(Pulmozyme—rHu-DNAase-), other proteins (Clotting factors, Interleukins,Albumin), gene therapy and RNAi, cell therapy (Provenge—Prostate cancervaccine), antibody drug conjugates—Adcetris (Brentuximab vedotin forHL), cytokines, anti-infective agents, polynucleotides, oligonucleotides(e.g., gene vectors), or any combination thereof or solid droplets orsuspensions such as Flonase (fluticasone propionate) or Advair(fluticasone propionate and salmeterol xinafoate).

In other embodiments, the in-line droplet delivery device with a smallvolume drug ampoule may be used for the treatment or prevention ofpulmonary diseases or disorders such as asthma, chronic obstructivepulmonary diseases (COPD) cystic fibrosis (CF), tuberculosis, chronicbronchitis, or pneumonia. In certain embodiments, the in-line dropletdelivery device may be used to deliver therapeutic agents such as COPDmedications, asthma medications, or antibiotics. By way of non-limitingexample, such therapeutic agents include albuterol sulfate, ipratropiumbromide, tobramycin, fluticasone propionate, fluticasone furoate,tiotropium, glycopyrrolate, olodaterol, salmeterol, umeclidinium, andcombinations thereof.

In other embodiments, the in-line droplet delivery device with a smallvolume drug ampoule of the disclosure may be used to deliver a solutionof nicotine including the water-nicotine azeotrope for the delivery ofhighly controlled dosages for smoking cessation or a condition requiringmedical or veterinary treatment. In addition, the fluid may contain THC,CBD, or other chemicals contained in marijuana for the treatment ofseizures and other conditions.

In certain embodiments, the in-line drug delivery device with a smallvolume drug ampoule of the disclosure may be used to deliver scheduledand controlled substances such as narcotics for the highly controlleddispense of pain medications where dosing is monitored or otherwisecontrolled. In certain embodiments, by way of non-limiting example,dosing may only enabled by doctor or pharmacy communication to thedevice, only in a specific location such as the patient's residence asverified by GPS location on the patient's smart phone, and/or it may becontrolled by monitoring compliance with dosing schedules, amounts,abuse compliances, etc. In certain aspects, this mechanism of highlycontrolled dispensing of controlled medications can prevent the abuse oroverdose of controlled substances.

Certain benefits of the pulmonary route for delivery of drugs and othermedications include a non-invasive, needle-free delivery system that issuitable for delivery of a wide range of substances from small moleculesto very large proteins, reduced level of metabolizing enzymes comparedto the GI tract and absorbed molecules do not undergo a first passeffect. (A. Tronde, et al., J Pharm Sci, 92 (2003) 1216-1233; A. L.Adjei, et al., Inhalation Delivery of Therapeutic Peptides and Proteins,M. Dekker, New York, 1997). Further, medications that are administeredorally or intravenously are diluted through the body, while medicationsgiven directly into the lungs may provide concentrations at the targetsite (the lungs) that are about 100 times higher than the sameintravenous dose. This is especially important for treatment of drugresistant bacteria, drug resistant tuberculosis, for example and toaddress drug resistant bacterial infections that are an increasingproblem in the ICU.

Another benefit for giving medication directly into the lungs is thathigh, toxic levels of medications in the blood stream their associatedside effects can be minimized. For example intravenous administration oftobramycin leads to very high serum levels that are toxic to the kidneysand therefore limits its use, while administration by inhalationsignificantly improves pulmonary function without severe side effects tokidney functions. (Ramsey et al., Intermittent administration of inhaledtobramycin in patients with cystic fibrosis. N Engl J Med 1999;340:23-30; MacLusky et al., Long-term effects of inhaled tobramycin inpatients with cystic fibrosis colonized with Pseudomonas aeruginosa.Pediatr Pulmonol 1989; 7:42-48; Geller et al., Pharmacokinetics andbioavailablility of aerosolized tobramycin in cystic fibrosis. Chest2002; 122:219-226.)

As discussed above, effective delivery of droplets deep into the lungairways require droplets that are less than about 5-6 microns indiameter, specifically droplets with mass mean aerodynamic diameters(MMAD) that are less than about 5 microns. The mass mean aerodynamicdiameter is defined as the diameter at which 50% of the droplets by massare larger and 50% are smaller. In certain aspects of the disclosure, inorder to deposit in the alveolar airways, droplets in this size rangemust have momentum that is sufficiently high to permit ejection out ofthe device, but sufficiently low to overcome deposition onto the tongue(soft palate) or pharynx.

In other aspects of the disclosure, methods for generating an ejectedstream of droplets for delivery to the pulmonary system of user usingthe droplet delivery devices of the disclosure are provided. In certainembodiments, the ejected stream of droplets is generated in acontrollable and defined droplet size range. By way of example, thedroplet size range includes at least about 50%, at least about 60%, atleast about 70%, at least about 85%, at least about 90%, between about50% and about 90%, between about 60% and about 90%, between about 70%and about 90%, between about 70% and about 95%, etc., of the ejecteddroplets are in a respirable range of below about 6 μm, preferably belowabout 5 μm.

In other embodiments, the ejected stream of droplets may have one ormore diameters, such that droplets having multiple diameters aregenerated so as to target multiple regions in the airways (mouth,tongue, throat, upper airways, lower airways, deep lung, etc.) By way ofexample, droplet diameters may range from about 1 μm to about 200 μm,about 2 μm to about 100 μm, about 2 μm to about 60 μm, about 2 μm toabout 40 μm, about 2 μm to about 20 μm, about 1 μm to about 5 μm, about1 μm to about 4.7 μm, about 1 μm to about 4 μm, about 10 μm to about 40μm, about 10 μm to about 20 μm, about 5 μm to about 10 μm, andcombinations thereof. In particular embodiments, at least a fraction ofthe droplets have diameters in the respirable range, while otherdroplets may have diameters in other sizes so as to targetnon-respirable locations (e.g., larger than about 5 μm). Illustrativeejected droplet streams in this regard might have 50%-70% of droplets inthe respirable range (less than about 5 μm), and 30%-50% outside of therespirable range (about 5-about 10 μm, about 5-about 20 μm, etc.)

In another embodiment, methods for delivering safe, suitable, andrepeatable dosages of a medicament to the pulmonary system using thedroplet delivery devices of the disclosure are provided. The methodsdeliver an ejected stream of droplets to the desired location within thepulmonary system of the subject, including the deep lungs and alveolarairways.

In certain aspects of the disclosure, an in-line droplet delivery devicewith a small volume drug ampoule for delivery an ejected stream ofdroplets to the pulmonary system of a subject is provided. The in-linedroplet delivery device with a small volume drug ampoule generallyincludes a housing, a mouthpiece positioned at the airflow exit side ofthe housing, a small volume drug ampoule disposed in or in fluidcommunication with the housing including a drug reservoir for receivinga small volume of fluid, an ejector mechanism in fluid communicationwith the reservoir, and at least one differential pressure sensorpositioned within the housing. In certain embodiments, the small volumedrug ampoule may include a reservoir which comprises an internalflexible membrane separating two internal volumes, a first backgroundpressure fluid volume and a second drug volume. The housing, itsinternal components, and various device components (e.g., themouthpiece, air inlet flow element, etc.) are orientated in asubstantially in-line or parallel configuration (e.g., along the airflowpath) so as to form a small, hand-held device. The differential pressuresensor is configured to electronically breath activate the ejectormechanism upon sensing a pre-determined pressure change within themouthpiece, and the ejector mechanism is configured to generate anejected stream of droplets.

In certain embodiments, the mouthpiece may be interfaced with (andoptionally removable and/or replaceable), integrated into, or part ofthe housing. In other embodiments, the mouthpiece may be interfaced with(and optionally removable and/or replaceable), integrated into, or partof the drug delivery ampoule.

The ejector mechanism may include a piezoelectric actuator which isdirectly or indirectly coupled to an aperture plate having a pluralityof openings formed through its thickness. The piezoelectric actuator isoperable to directly or indirectly oscillate the aperture plate at afrequency to thereby generate an ejected stream of droplets.

In certain embodiments, the housing and ejector mechanism are orientedsuch that the exit side of aperture plate is perpendicular to thedirection of airflow and the stream of droplets is ejected in parallelto the direction of airflow. In other embodiments, the housing andejector mechanism are oriented such that the exit side of aperture plateis parallel to the direction of airflow and the stream of droplets isejected substantially perpendicularly to the direction of airflow suchthat the ejected stream of droplets is directed through the housing atan approximate 90 degree change of trajectory prior to expulsion fromthe housing.

In certain embodiments, the in-line droplet delivery device with a smallvolume drug ampoule is comprised of a separate small volume drugdelivery ampoule with an ejector mechanism (e.g., combinationreservoir/ejector mechanism module) embedded within a surface of a drugreservoir, and a handheld base unit (e.g., housing) including adifferential pressure sensor, a microprocessor and three AAA batteries.In certain embodiments, the handheld base unit also includes amouthpiece, optionally removable, an optional mouthpiece cover, and anoptional ejector plate seal. The microprocessor controls dose delivery,dose counting and software designed monitoring parameters that can betransmitted through bluetooth technology. The ejector mechanismoptimizes droplet delivery to the lungs by creating an ejected dropletstream in a predefined range with a high degree of accuracy andrepeatability. Initial droplet studies show at least 65% to 70% ofdroplets ejected from the device are in the respirable range (e.g., 1-5μm).

In certain embodiments, the in-line droplet delivery device with a smallvolume drug ampoule may include a combination reservoir/ejectormechanism module (e.g., the small volume drug delivery ampoule) that maybe replaceable or disposable either on a periodic basis, e.g., a daily,weekly, monthly, as-needed, etc. basis, as may be suitable for aprescription or over-the-counter medication. The reservoir may beprefilled and stored in a pharmacy for dispensing to patients or filledat the pharmacy or elsewhere by using a suitable injection means such asa hollow injection syringe driven manually or driven by a micro-pump.The syringe may fill the reservoir by pumping fluid into or out of arigid container or other collapsible or non-collapsible reservoir. Incertain aspects, such disposable/replaceable, combinationreservoir/ejector mechanism module may minimize and prevent buildup ofsurface deposits or surface microbial contamination on the apertureplate, owing to its short in-use time.

In certain aspects of the disclosure, the ejector mechanism, smallvolume drug reservoir, and housing/mouthpiece function to generate aplume with droplet diameters less than about 5 um. As discussed above,in certain embodiments, the small volume reservoir and ejector mechanismmodules are powered by electronics in the device housing and a reservoirwhich may carry sufficient drug for a single dose, just a few doses, orseveral hundred doses of medicament.

The present disclosure also provides an in-line droplet delivery devicewith a small volume drug ampoule that is altitude insensitive. Incertain implementations, the in-line droplet delivery device with asmall volume drug ampoule is configured so as to be insensitive topressure differentials that may occur when the user travels from sealevel to sub-sea levels and at high altitudes, e.g., while traveling inan airplane where pressure differentials may be as great as 4 psi. Aswill be discussed in further detail herein, in certain implementationsof the disclosure, the in-line droplet delivery device may include asuperhydrophobic filter, optionally in combination with a spiral vaporbarrier, which provides for free exchange of air into and out of thereservoir, while blocking moisture or fluids from passing into thereservoir, thereby reducing or preventing fluid leakage or deposition onaperture plate surfaces.

In certain aspects, the devices of the disclosure eliminate the need forpatient/device coordination by using a differential pressure sensor toinitiate the piezoelectric ejector in response to the onset ofinhalation. The device does not require manual triggering of medicationdelivery. Unlike propellant driven MDIs, the droplets from the devicesof the disclosure are generated having little to no intrinsic velocityfrom the aerosol formation process and are inspired into the lungssolely by the user's incoming breath passing through the mouthpiece. Thedroplets will ride on entrained air providing improved deposition in thelung.

In certain embodiments, as described in further detail herein, when thedrug ampoule is mated to the handheld base unit, electrical contact ismade between the base containing the batteries and the ejector mechanismembedded in the drug reservoir. In certain embodiments, visualindications, e.g., a horizontal series of three user visible LED lights,and audio indications via a small speaker within the handheld base unitmay provide user notifications. By way of example, the device may be,e.g., 2.0-3.5 cm high, 5-7 cm wide, 10.5-12 cm long and may weightapproximately 95 grams with an empty drug ampoule and with batteriesinserted.

As described herein, in certain embodiments, the in-line dropletdelivery device with a small volume drug ampoule may be turned on andactivated for use by inserting the drug ampoule into the base unit,opening the mouthpiece cover, and/or switching an on/off switch/slidebar. In certain embodiments, visual and/or audio indicators may be usedto indicate the status of the device in this regard, e.g., on, off,stand-by, preparing, etc. By way of example, one or more LED lights mayturn green and/or flash green to indicate the device is ready for use.In other embodiments, visual and/or audio indicators may be used toindicate the status of the drug ampoule, including the number of dosestaken, the number of doses remaining, instructions for use, etc. Forexample, and LED visual screen may indicate a dose counter numericaldisplay with the number of remaining doses in the reservoir.

As described in further detail herein, during use as a user inhalesthrough the mouthpiece of the housing of an in-line droplet deliverydevice of the disclosure, a differential pressure sensor within thehousing detects inspiratory flow, e.g., by measuring the pressure dropacross a Venturi plate at the back of the mouthpiece. When a thresholdpressure decline (e.g., 8 slm) is attained, the microprocessor activatesthe ejector mechanism, which in turn generates an ejected stream ofdroplets into the airflow of the device that the user inhales throughthe mouthpiece. In certain embodiments, audio and/or visual indicatesmay be used to indicate that dosing has been initiated, e.g., one ormore LEDs may illuminate green. The microprocessor then deactivates theejector at a designated time after initiation so as to achieve a desiredadministration dosage, e.g., 1-1.45 seconds. In certain embodiments, asdescribed in further detail herein, the device may provide visual and/oraudio indicators to facilitate proper dosing, e.g., the device may emita positive chime sound after the initiation of dosing, indicating to theuser to begin holding their breath for a designated period of time,e.g., 10 seconds. During the breath hold period, e.g., the three greenLEDs may blink. Additionally, there may be voice commands instructingthe patient on proper times to exhale, inhale and hold their breath,with an audio indicator of a breath hold countdown.

Following dosing, the in-line droplet delivery device with a smallvolume drug ampoule may turned off and deactivated in any suitablemanner, e.g., by closing the mouthpiece cover, switching an on/offswitch/slide bar, timing out from non-use, removing the drug ampoule,etc. If desired, audio and/or visual indicators may prompt a user todeactivate the device, e.g., by flashing one or more red LED lights,providing voice commands to close the mouthpiece cover, etc.

In certain embodiments, the in-line droplet delivery device with a smallvolume drug ampoule may include an ejector mechanism closure system thatseals the aperture plate when not in use to protect the integrity of theaperture plate and to minimize and prevent contamination and evaporationof the fluid within the reservoir. For example, in some embodiments, thedevice may include a mouthpiece cover that comprises a rubber plug thatis sized and shaped to seal the exit side surface of the aperture platewhen the cover is closed. In other embodiments, the mouthpiece cover maytrigger a slide to seal the exit side surface of the aperture plate whenthe cover is closed. Other embodiments and configurations are alsoenvisioned, e.g., manual slides, covers, and plugs, etc. In certainaspects, the microprocessor may be configured to detect when the ejectormechanism closure, aperture plate seal, etc. is in place, and maythereafter deactivate the device.

Several features of the device allow precise dosing of specific dropletsizes. Droplet size is set by the diameter of the holes in the meshwhich are formed with high accuracy. By way of example, the holes in theaperture plate may range in size from 1 μm to 6 μm, from 2 μm to 5 μm,from 3 μm to 5 μm, from 3 μm to 4 μm, etc. Ejection rate, in dropletsper second, is generally fixed by the frequency of the aperture platevibration, e.g., 108-kHz, which is actuated by the microprocessor. Incertain embodiments, there is less than a 50-millisecond lag between thedetection of the start of inhalation and full droplet generation.

Other aspects of the device of the disclosure that allow for precisedosing of specific droplet sizes include the production of dropletswithin the respirable range early in the inhalation cycle, therebyminimizing the amount of drug product being deposited in the mouth orupper airways at the end of an inhalation. In addition, the design ofthe drug ampoule allows the aperture plate surface to be wetted andready for ejection without user intervention, thus obviating the needfor shaking and priming. Further, the design of the drug ampoule ventconfiguration together with the ejector mechanism closure system limitsfluid evaporation from the reservoir to less than 150 μL to 350 μL permonth.

The device may be constructed with materials currently used in FDAcleared devices. Standard manufacturing methods may be employed tominimize extractables.

Any suitable material may be used to form the housing of the dropletdelivery device. In particular embodiment, the material should beselected such that it does not interact with the components of thedevice or the fluid to be ejected (e.g., drug or medicament components).For example, polymeric materials suitable for use in pharmaceuticalapplications may be used including, e.g., gamma radiation compatiblepolymer materials such as polystyrene, polysulfone, polyurethane,phenolics, polycarbonate, polyimides, aromatic polyesters (PET, PETG),etc.

The small volume drug ampoule may be constructed of any suitablematerials for the intended pharmaceutical use. In particular, the drugcontacting portions may be made from material compatible with thedesired active agent(s). By way of example, in certain embodiments, thedrug only contacts the inner side of the drug reservoir and the innerface of the aperture plate and piezoelectric element. Wires connectingthe piezoelectric ejector mechanism to the batteries contained in thebase unit may be embedded in the drug ampoule shell to avoid contactwith the drug. The piezoelectric ejector may be attached to the drugreservoir by a flexible bushing. To the extent the bushing may contactthe drug fluid, it may be, e.g., any suitable material known in the artfor such purposes such as those used in piezoelectric nebulizers.

Any suitable material known in the art for use in connection withpharmaceutical applications may be used as the ampoule internalmembrane, such that the membrane does not interact with the drug fluidor the background pressure fluid, e.g., non-reactive polymer materials.In certain aspects, the membrane is a flexible polymer material, andmoves in a direction towards the ejector mechanism surface during use,as the drug fluid is ejected so as to avoid the creation of negativepressure in the drug volume during use. In certain embodiments, themembrane may include pleats or other directional etchings to focuspressure above the area above the ejector mechanism to therebyfacilitate an increase in mass loading of the drug fluid to the ejectormechanism, as described below.

Any suitable fluid known in the art for use in connection withpharmaceutical applications may be selected as the background pressurefluid, including but not limited to, saline, distilled water, PBSsolution, etc. In certain embodiments, it may be desirable to select abackground pressure fluid with similar or the same density as thetherapeutic agent fluid so as to substantially match mass loading of thebackground pressure fluid to that of the therapeutic agent fluid.Without intending to be limited by theory, the background pressurevolume of fluid helps to provide a sufficient mass loading of the drugfluid to the ejector mechanism surface. In this regard, insufficientmass loading may result in inefficient wetting of the ejector surfaceand inefficient ejection of the drug fluid.

In certain embodiments, the device mouthpiece may be removable,replaceable and may be cleaned. Similarly, the device housing and drugampoule can be cleaned by wiping with a moist cloth. In certainembodiments, the mouthpiece may be interfaced with (and optionallyremovable and/or replaceable), integrated into, or part of the housing.In other embodiments, the mouthpiece may be interfaced with (andoptionally removable and/or replaceable), integrated into, or part ofthe drug delivery ampoule.

Again, any suitable material may be used to form the mouthpiece of thedroplet delivery device. In particular embodiment, the material shouldbe selected such that it does not negatively interact with thecomponents of the device or the fluid to be ejected (e.g., drug ormedicament components). For example, polymeric materials suitable foruse in pharmaceutical applications may be used including, e.g., gammaradiation compatible polymer materials such as polystyrene, polysulfone,polyurethane, phenolics, polycarbonate, polyimides, aromatic polyesters(PET, PETG), etc. In certain embodiments, the mouthpiece may beremovable, replaceable and sterilizable. This feature improvessanitation for drug delivery by providing a mechanism to minimizebuildup of aerosolized medication within the mouthpiece and by providingfor ease of replacement, disinfection and washing. In one embodiment,the mouthpiece tube may be formed from sterilizable and transparentpolymer compositions such as polycarbonate, polyethylene orpolypropylene, as discussed herein.

In certain aspects of the disclosure, an electrostatic coating may beapplied to the one or more portions of the housing, e.g., inner surfacesof the housing along the airflow pathway such as the mouthpiece, to aidin reducing deposition of ejected droplets during use due toelectrostatic charge build-up. Alternatively, one or more portions ofthe housing may be formed from a charge-dissipative polymer. Forinstance, conductive fillers are commercially available and may becompounded into the more common polymers used in medical applications,for example, PEEK, polycarbonate, polyolefins (polypropylene orpolyethylene), or styrenes such as polystyrene oracrylic-butadiene-styrene (ABS) copolymers. Alternatively, in certainembodiments, one or more portions of the housing, e.g., inner surfacesof the housing along the airflow pathway such as the mouthpiece, may becoated with anti-microbial coatings, or may be coated with hydrophobiccoatings to aid in reducing deposition of ejected droplets during use.Any suitable coatings known for such purposes may be used, e.g.,polytetrafluoroethylene (Teflon).

Any suitable differential pressure sensor with adequate sensitivity tomeasure pressure changes obtained during standard inhalation cycles maybe used, e.g., ±5 SLM, 10 SLM, 20 SLM, etc. For instance, pressuresensors from Sensirion, Inc., SDP31 or SDP32 (U.S. Pat. No. 7,490,511B2) are particularly well suited for these applications.

In certain aspects, the microprocessor in the device may be programmedto ensure exact timing and actuation of the ejector mechanism inaccordance with desired parameters, e.g., based duration ofpiezoelectric activation to achieve desired dosages, etc. In certainembodiments, the device includes or interfaces with a memory (on thedevice, smartphone, App, computer, etc.) to record the date-time of eachejection event, as well as the user's inhalation flow rate during thedose inhalation to facilitate user monitoring, as well as drug ampouleusage monitoring. For instance, the microprocessor and memory canmonitor doses administered and doses remaining in a particular drugampoule. In certain embodiments, the drug ampoule may comprisecomponents that include identifiable information, and the base unit maycomprise components that may “read” the identifiable information tosense when a drug ampoule has been inserted into the base unit, e.g.,based on a unique electrical resistance of each individual ampoule, anRFID chip, or other readable microchip (e.g., cryptoauthenticationmicrochip). Dose counting and lockouts may also be preprogramed into themicroprocessor.

In certain embodiments of the present disclosure, the signal generatedby the pressure sensors provides a trigger for activation and actuationof the ejector mechanism to thereby generate droplets and deliverydroplets at or during a peak period of a patient's inhalation(inspiratory) cycle and assures optimum deposition of the plume ofdroplets and delivery of the medication into the pulmonary airways ofthe user.

In accordance with certain aspects of the disclosure, the in-linedroplet delivery device with a small volume drug ampoule provides areliable monitoring system that can date and time stamp actual deliveryof medication, e.g., to benefit patients through self-monitoring orthrough involvement of care givers and family members.

As described in further detail herein, the in-line droplet deliverydevice with a small volume drug ampoule of the disclosure may detectinspiratory airflow and record/store inspiratory airflow in a memory (onthe device, smartphone, App, computer, etc.). A preset threshold (e.g.,8-10 slm) triggers delivery of medication over a defined period of time,e.g., 1-1.5 seconds. Inspiratory flow is sampled frequently until flowstops. The number of times that delivery is triggered is incorporatedand displayed in the dose counter LED on the device. Blue toothcapabilities permit the wireless transmission of the data.

Bluetooth communication in the device will communicate date, time andnumber of actuations per session to the user's smartphone. Softwareprogramming can provide charts, graphics, medication reminders andwarnings to patients and whoever is granted permission to the data. Thesoftware application will be able to incorporate multiple medicationsthat use the device of the disclosure (e.g. albuterol, inhaled steroid,etc.). The device of the disclosure can also provide directedinstruction to users, including audio and visual indicators tofacilitate proper use of the device and proper dosing.

The device of the present disclosure is configured to dispense dropletsduring the correct part of the inhalation cycle, and can includinginstruction and/or coaching features to assist patients with properdevice use, e.g., by instructing the holding of breath for the correctamount of time after inhalation. The device of the disclosure allowsthis dual functionality because it may both monitor air flow during theinhalation, and has internal sensors/controls which may detect the endof inhalation (based upon measured flow rate) and can cue the patient tohold their breath for a fixed duration after the inhalation ceases.

In one exemplary embodiment, a patient may be coached to hold theirbreath with an LED that is turned on at the end of inhalation and turnedoff after a defined period of time (i.e., desired time period of breathhold), e.g., 10 seconds. Alternatively, the LED may blink afterinhalation, and continue blinking until the breath holding period hasended. In this case, the processing in the device detects the end ofinhalation, turns on the LED (or causes blinking of the LED, etc.),waits the defined period of time, and then turns off the LED. Similarly,the device can emit audio indications, e.g., one or more bursts of sound(e.g., a 50 millisecond pulse of 1000 Hz), verbal instructions to holdbreath, verbal countdown, music, tune, melody, etc., at the end ofinhalation to cue a patient to hold their breath for the during of thesound signals. If desired, the device may also vibrate during or uponconclusion of the breath holding period.

In certain embodiments, the device provides a combination of audio andvisual methods (or sound, light and vibration) described above tocommunicate to the user when the breath holding period has begun andwhen it has ended. Or during the breath holding to show progress (e.g.,a visual or audio countdown).

In other aspects, the device of the disclosure may provide coaching toinhale longer, more deeply, etc. The average peak inspiratory flowduring inhalation (or dosing) can be utilized to provide coaching. Forexample, a patient may hear a breath deeper command until they reach 90%of their average peak inspiratory flow as measured during inspiration(dosing) as stored on the device, phone or in the cloud.

In addition, an image capture device, including cameras, scanners, orother sensors without limitation, e.g. charge coupled device (CCD), maybe provided to detect and measure the ejected aerosol plume. Thesedetectors, LED, delta P transducer, CCD device, all provide controllingsignals to a microprocessor or controller in the device used formonitoring, sensing, measuring and controlling the ejection of a plumeof droplets and reporting patient compliance, treatment times, dosage,and patient usage history, etc., via Bluetooth, for example.

Reference will now be made to the figures, with like componentsillustrates with like references numbers.

FIGS. 1A and 1B illustrate an exemplary in-line droplet delivery devicewith a small volume drug ampoule of the disclosure, with FIG. 1A showingthe in-line droplet delivery device 100 having a mouthpiece cover 102 inthe closed position, and FIG. 1B having a mouthpiece cover 102 in theopen position. As shown, the droplet delivery device is configured in anin-line orientation in that the housing, its internal components, andvarious device components (e.g., the mouthpiece, air inlet flow element,etc.) are orientated in a substantially in-line or parallelconfiguration (e.g., along the airflow path) so as to form a small,hand-held device.

In the embodiment shown in FIGS. 1A and 1B, the in-line droplet deliverydevice 100 includes a base unit 104 and a small volume drug deliveryampoule 106. As illustrated in this embodiment, and discussed in furtherdetail herein, the small volume drug delivery ampoule 106 slides intothe front of the base unit 104 via slides 112. In certain embodiments,mouthpiece cover 102 may include a push element 102 a that facilitatesinsertion of drug delivery ampoule 106. Also illustrated are one or moreairflow entrances or openings 110. By way of example, there may beairflow entrances on the opposite side of the device, multiple airflowentrances on the same side of the device, or a combination thereof (notshown). The in-line droplet delivery device 100 also includes mouthpiece108 at the airflow exit side of the device.

With reference to FIG. 2, an exploded view of the exemplary in-linedroplet delivery device of FIGS. 1A and 1B is shown, including internalcomponents of the housing including a power/activation button 201; anelectronics circuit board 202; a small volume drug delivery ampoule 106that comprises an ejector mechanism and reservoir (not shown, describedfurther herein); and a power source 203 (e.g., three AAA batteries,which may optionally be rechargeable) along with associated contacts 203a. In certain embodiments, the reservoir single use ampoule that may bereplaceable, disposable or reusable. Also shown, one or more pressuresensors 204 and optional spray sensors 205. In certain embodiments, thedevice may also include various electrical contacts 210 and 211 tofacilitate activation of the device upon insertion of drug deliveryampoule 106 into the base unit. Likewise, in certain embodiments, thedevice may include slides 212, posts 213, springs 214, and ampoule lock215 to facilitate insertion of drug delivery ampoule 106 into the baseunit.

The components may be packaged in a housing, and generally oriented inan in-line configuration. The housing may be disposable or reusable,single-dose or multi-dose. Although various configurations to form thehousing are within the scope of the disclosure, as illustrated in FIG.2, the housing may comprise a top cover 206, a bottom cover 207, and aninner housing 208. The housing may also include a power source housingor cover 209.

In certain embodiments, the device may include audio and/or visualindications, e.g., to provide instructions and communications to a user.In such embodiments, the device may include a speaker or audio chip (notshown), one or more LED lights 216, and LCD display 217 (interfaced withan LCD control board 218 and lens cover 219). The housing may behandheld and may be adapted for communication with other devices via aBluetooth communication module or similar wireless communication module,e.g., for communication with a subject's smart phone, tablet or smartdevice (not shown).

In certain embodiments, an air inlet flow element (not shown, see, e.g.,FIGS. 5A-5C and FIGS. 11A-18D) may be positioned in the airflow at theairflow entrance of the housing and configured to facilitatenon-turbulent (i.e., laminar and/or transitional) airflow across theexit side of aperture plate and to provide sufficient airflow to ensurethat the ejected stream of droplets flows through the droplet deliverydevice during use. In some embodiments, the air inlet flow element maybe positioned within the mouthpiece. Aspects of the present embodimentfurther allows customizing the internal pressure resistance of theparticle delivery device by allowing the placement of laminar flowelements having openings of different sizes and varying configurationsto selectively increase or decrease internal pressure resistance, aswill be explained in further detail herein.

By way of non-limiting example, an exemplary method of insertion of anampoule through to use and powering off of the device may be performedas follows:

-   -   1. When a new ampoule is initially inserted and pushed onto the        device slide guide the device door is open and the ampoule        slides and clicks into ampoule position 1. At this setting, an        aperture plate seal or cover on the ampoule is open and        electrical contacts on the device and ampoule make contact. The        system is powered ON and ready for breath actuation. When the        device door is opened, an audible beep may be emitted and LED        indicator(s) may turn green or flash to notify the user that the        system is ON and ready for dosing by inhaling through the        mouthpiece.    -   2. As a patient inhales, a pre-set pressure value is reached and        detected by the pressure sensor located within the housing        (e.g., delta P sensor) and a second audible indicator or LED        indicator may now indicate that a dose is triggered. After the        dose is triggered and delivered, another audible and/or LED        indicator may trigger until a spray cycle time of, e.g, 1-5        seconds (or other designated dosing time) ends. Further, if        desired, when a dose is delivered, the dose counter displayed on        the LCD will indicate that a dose was delivered by a decrease in        number of doses displayed on the LCD.    -   3. If no additional doses are required and a time of, e.g., 15        seconds elapse, an audible and/or LED indicator may trigger to        alert the user that the device is about to power-off, after        which time the device may enter into a low power, sleep mode.    -   4. If no additional doses are required, the device door is        closed to push the ampoule to the non-use position, the aperture        plate seal or cover is closed and the device is in placed sleep        mode. Further, as the slide mechanism releases pressure from the        ON/OFF switch, and the system is now OFF.    -   5. When a patient is ready to apply additional doses, the device        door is opened and the ampoule slides towards the mouthpiece as        it is pushed by a spring-loaded mechanism from the non-use        position to the use position, to thereby open the aperture plate        seal or cover.

More particularly, a specific exemplary embodiment of a mode ofoperation of insertion of a drug ampoule and operation of a device isillustrated in FIGS. 3A-1 to FIG. 3C-3. Referring to FIGS. 3A-1 and3A-2, when a small volume drug ampoule (1), is initially inserted andpushed onto the device slide guide (la), the device door (2) is open,the ampoule slides and clicks into ampoule position 1. An oval button(ampoule lock) (1 b) clicks down and snaps back to lock the ampoule inplace. At this setting, the seal on the aperture plate is open, the fourelectrical contacts on the device and ampoule make contact, and thesystem is powered ON, ready for breath actuation. The front two contacts(3) complete the circuit to actuate the piezoelectric element, while therear two contacts (4) are used to provide specific information on theampoule, such as ampoule ID, drug type, dosage, etc.

Referring to FIGS. 3B-1 and 3B-2, ampoule position 1(A) is shown, inwhich the oval button (1 b) locks the ampoule into place and the fourelectrical contacts, front (3) and rear (4) connect to complete theelectric circuit. When the ampoule is in position 1, the electroniccomponent that activates the ON/OFF button (1 c) is pushed by thespring-loaded, slide mechanism (5). FIG. 3B-1 provides a bottom view ofthe spring-loaded slide mechanism (5) and the ON/OFF button (1 c), inthe ON mode. FIG. 3B-2 provides an exploded view (5 a) of side bracketson the spring-loaded slide (5) and their position (5 a—dash arrows)through slots (5 b) on the device which make contact on the ampule (5 c)to push the ampule forward when the device door is opened and activatethe ON/OFF switch (1 c) as it makes contact with the ON/OFF button (1d). The device ON/OFF button (1 c) is activated by the slide (5) whenthe mouthpiece cover (2) is closed and pushes the ampule back toposition 2, where the aperture plate seal is in the closed position andpower is turned OFF to the device as pressure on the ON/OFF switch isreleased.

Referring to FIGS. 3C-1, 3C-2, and 3C-3, cross-sections of the devicewith the small volume ampoule (interior features not shown) inserted areillustrated to better illustrate the ampoule slide mechanism andpositioning of the ON/OFF switch. FIG. 3C-1 shows ampoule position 1,with the mouthpiece cover in the open position and the ON/OFF switch inthe ON position. FIG. 3C-2 shows ampoule position 2, with the mouthpiececover in the closed position and the ON/OFF switch in the OFF position.FIG. 3C-3 shows ampoule position 2, with the mouthpiece cover in theopen position and the ON/OFF switch in the OFF position.

However, it is noted that the devices and methods of the disclosure arenot so limited, and various modifications and expansions of the methodof operation is envisioned as within the scope of the disclosure.

For instance, the small volume drug ampoule may be used in a simple“snap-on” or “clip-in” configuration, which automatically activates thedevice. In particular, in the context of the small volume drug ampoule,as longer term use and storage of the fluid reservoir on the device isnot required, in certain embodiments, the small volume ampouleconfiguration may not require an aperture plate seal or cover in allembodiments, e.g., to maintain sterility and/or minimize evaporation ofthe therapeutic agent fluid. Further, in certain embodiments, the devicemay be configured, e.g., through on-board software, to prompt a user totake multiple breaths to ensure that the entire volume of therapeuticagent is ejected (e.g., through counting breath activations, monitoringvolume of ejected droplets, etc.). In such embodiments, the device maybe configured to ensure dosing accuracy is maintained.

In another embodiment, FIGS. 4A and 4B illustrate an alternative in-linedroplet delivery device with a small volume drug ampoule of thedisclosure, with FIG. 4A showing the in-line droplet delivery device 400with a base unit 404 having a mouthpiece cover 402 in the closedposition, and FIG. 4B with a base unit 404 having a mouthpiece cover 402in the open position. As shown, the droplet delivery device isconfigured in an in-line orientation in that the housing, its internalcomponents, and various device components (e.g., the mouthpiece, airinlet flow element, etc.) are orientated in a substantially in-line orparallel configuration (e.g., along the airflow path) so as to form asmall, hand-held device.

In the embodiment shown in FIGS. 4A and 4B, the in-line droplet deliverydevice 400 includes a base unit 404 and a small volume drug deliveryampoule 406. As illustrated in this embodiment, and discussed in furtherdetail herein, the small volume drug delivery ampoule 406 slides intothe front of the base unit 404. In certain embodiments, mouthpiece cover402 may include aperture plate plug 412. Also illustrated are one ormore airflow entrances or openings 410 in mouthpiece 408. By way ofexample, there may be airflow entrances on the opposite side of thedevice, multiple airflow entrances on the same side of the device, or acombination thereof (not shown). The in-line droplet delivery device 400also includes mouthpiece 408 at the airflow exit side of the device.

With reference to FIG. 5, an exploded view of the exemplary in-linedroplet delivery device of FIGS. 4A and 4B is shown, including internalcomponents of the housing including an electronics circuit board 502; asmall volume drug delivery ampoule 406 that comprises top cover 430having optional vents 431 and vapor barriers 432, an ejector mechanism434, a reservoir (interior features not shown) 435, electrical contacts436, and one or more sensor ports 437; and a power source 503 (e.g.,three AAA batteries, which may optionally be rechargeable). In certainembodiments, the device may also include various electrical contacts 442and sensor ports 444 to facilitate activation of the device uponinsertion of drug delivery ampoule 406 into the base unit 404. Likewise,in certain embodiments, the device may include resistors or chips 504 tofacilitate insertion and detection of drug delivery ampoule 406 into thebase unit 404.

In certain embodiments, the reservoir may be a single use reservoir thatmay be replaceable, disposable or reusable. As illustrated in FIG. 5, incertain embodiments, the small volume drug delivery ampoule may alsocomprise or be interfaced with a mouthpiece 408 and a mouthpiece cover402. As shown, ejector mechanism 434 may be positioned in line withmouthpiece 408 and reservoir 435 such that the exit side of the apertureplate is perpendicular to the direction of airflow and the stream ofdroplets is ejected in parallel to the direction of airflow. Themouthpiece cover 402 may further include an aperture plate plug 412.

The components may be packaged in a housing, and generally oriented inan in-line configuration. The housing may be disposable or reusable,single-dose or multi-dose. Although various configurations to form thehousing are within the scope of the disclosure, as illustrated in FIG.5, the housing may comprise a top cover 506, a bottom cover 507, and aninner housing 508. The device may also include one or more ampoulerelease buttons 550, e.g., positioned on the side of the housing tofacilitate release of the drug delivery ampoule 406 once inserted intothe base unit 404.

In certain embodiments, the device may include audio and/or visualindications, e.g., to provide instructions and communications to a user.In such embodiments, the device may include a speaker or audio chip 520,one or more LED lights 516, and LCD display 517 (interfaced with an LCDcontrol board 518 and lens cover 519). The housing may be handheld andmay be adapted for communication with other devices via a Bluetoothcommunication module or similar wireless communication module, e.g., forcommunication with a subject's smart phone, tablet or smart device (notshown).

With reference to FIG. 6, a cross-section of an in-line device of FIGS.4A and 4B is shown to illustrate an exemplary configuration of overallshape of the interior of reservoir 435 and its relation to ejectormechanism 434 (additional interior features not shown). As shown,reservoir 435 may be sized and shaped such that the volume of fluid heldwithin the reservoir is funneled and directed to the ejection surface ofthe aperture plate during use. More particularly, as shown, the bottomsurface of the reservoir may be sloped towards the ejector mechanism soas to facilitate flow of the fluid within the drug reservoir during use.Without intending to be limited by theory, such configurations may beparticularly suited for device orientations wherein the ejectormechanism is oriented perpendicularly to the direction of airflow.However, it is noted that the disclosure is not so limited, and variousshapes, sizes and configurations of ampoule are envisioned as within thescope of the disclosure.

FIG. 7 illustrates the base unit 404 of the embodiment of FIGS. 4A and4B without the drug delivery ampoule inserted. Without the drug deliveryampoule inserted, tracks 440 for directing the ampoule into place,electrical contacts 442, and sensor port 444 are shown. Also shown isrelease button 450.

FIGS. 8A and 8B illustrate a small volume drug delivery ampoule 406 withmouthpiece cover 402 attached and in a closed position in front view(FIG. 8A) and back view (FIG. 8B). FIG. 8B illustrates electricalcontacts 436 and sensor port 437 of the ampoule, as well as protrudingslides 452 to facilitate placement of the ampoule into tracks 440 duringinsertion. By way of example, when small volume drug delivery ampoule406 is inserted into base unit 404, protruding slides 452 mate withtracks 440, sensor port 437 mates with sensor port 444, and electricalcontacts 436 mates with electrical contacts 442. The small volume drugdelivery ampoule is pushed into the base unit and locked into place withthe protruding slides and tracks engaging one another. During use, apressure sensor located on the control board senses pressure changeswithin the device via the pressure sensing ports (e.g., within themouthpiece). To facilitate detection of pressure changes, the base unitincludes a second pressure sensing port and outside channel (not shown)to facilitate sensing of reference or ambient pressure.

FIG. 9 illustrates a cross-section of an exemplary small volume drugampoule 406. As shown, the small volume drug ampoule 406 includes amembrane 920, which separates the reservoir into two volumes, a firstbackground pressure fluid volume 925, and a second drug fluid volume930. The small volume ampoule may also include an air exchange vent(e.g., a superhydrophobic filter) 935, and an option fill port 940. Anysuitable size and shape configuration of reservoir may be used. By wayof non-limiting example, for 20 uL dose on a 5 mm ejector, a smallvolume ampoule may be sized and shaped so as to be 5 mm diameter by 1 mmhigh well.

As discussed herein, the drug reservoir and/or small volume drug ampoulemay include various vents and/or vapor barriers to facilitate venting,etc. With reference to FIGS. 10A-10C, an exemplary reservoir or ampouleis shown which is configured so as to be insensitive to pressuredifferentials that may occur when the user travels from sea level tosub-sea levels and at high altitudes, e.g., while traveling in anairplane where pressure differentials may be as great as 4 psi. Asshown, FIG. 10A shows a perspective view of an exemplary ampoule 900.FIGS. 10B and 10C show exploded view of ampoule 900 from perspective topand bottom views. With reference to FIGS. 10B and 10C, the ampoule 900generally includes a top cover 901 and a bottom cover 902. The ampoule900 may be configured to include one or more superhydrophobic filter(s)904 covering one or more vents 906, and the fluid reservoir housing mayinclude a spiral channel (or similarly shaped) vapor barrier 905, whichprovides for free exchange of air into and out of the fluid reservoir,while blocking moisture or fluids from passing into the reservoir,thereby reducing or preventing fluid leakage or deposition on apertureplate surfaces. If desired, one or more O-rings 903, or similar sealingmechanism, may be used to form a seal between the top cover 901 and thebottom cover 902 in connection with the vapor barrier 905. Withoutintending to be limited, the superhydrophobic filter and vent maygenerally allow for the venting of air and equilibration of air pressurewithin the fluid reservoir, while maintaining a sterile environmentwithin the fluid reservoir. The spiral channel vapor barrier willgenerally prevent the transfer of moisture to and from the fluidreservoir (e.g., through the vent opening).

In accordance with aspects, the in-line droplet delivery devices withsmall volume drug ampoules of the disclosure may include an air inletflow element (see, e.g., FIGS. 11A-11C and 13A-20D) which may bepositioned in the airflow at the airflow entrance of the device andconfigured to facilitate non-turbulent (i.e., laminar and/ortransitional) airflow across the exit side of aperture plate and toprovide sufficient airflow to ensure that the ejected stream of dropletsflows through the droplet delivery device during use. In someembodiments, the air inlet flow element may be positioned within themouthpiece. Aspects of the present embodiment further allows customizingthe internal pressure resistance of the particle delivery device byallowing the placement of laminar flow elements having openings ofdifferent sizes and varying configurations to selectively increase ordecrease internal pressure resistance, as will be explained in furtherdetail herein.

In accordance with certain embodiments of the in-line droplet deliverydevice with small volume drug ampoules of the disclosure, the device mayinclude an air inlet flow element may be positioned in the airflow atthe airflow entrance of the device and configured to facilitatenon-turbulent (i.e., laminar and/or transitional) airflow across theexit side of aperture plate and to provide sufficient airflow to ensurethat the ejected stream of droplets flows through the droplet deliverydevice during use. In some embodiments, the air inlet flow element maybe positioned within the mouthpiece. In addition, the air inlet flowelement allows for customization of internal device pressure resistanceby designing openings of different sizes and varying configurations toselectively increase or decrease internal pressure resistance.

As will be described in further detail herein, the air inlet flowelement may be positioned behind the exit side of the aperture platealong the direction of airflow, or in-line or in front of the exit sideof the aperture plate along the direction of airflow. In certainembodiments, the air inlet flow element comprises one or more openingsformed there through and configured to increase or decrease internalpressure resistance within the droplet delivery device during use. Forinstance, the air inlet flow element comprises an array of one oropenings. In the embodiments, the air inlet flow element comprises oneor more baffles, e.g., wherein the one or more baffles comprise one ormore airflow openings.

In certain embodiments, the air inlet flow element is designed andconfigured in order to provide an optimum airway resistance forachieving peak inspirational flows that are required for deep inhalationwhich promotes delivery of ejected droplets deep into the pulmonaryairways. Air inlet flow elements also function to promote non-turbulentflow across the aerosol plume exit port, which also serves to stabilizeairflow repeatability, stability and insures an optimal precision in thedelivered dose.

Without intending to be limited by theory, in accordance with aspects ofthe disclosure, the size, number, shape and orientation of flowrestrictions (e.g., openings, holes, flow blocks, etc.) in the air inletflow element of the disclosure may be configured to provide a desiredpressure drop within the in-line droplet delivery device. In certainembodiments, it may be generally desirable to provide a pressure dropthat is not so large as to strongly affect a user's breathing orperception of breathing.

In certain implementations, the use of air inlet flow elements havingdifferently configured, sized, and shaped flow restrictions (e.g.,openings, holes, flow blocks, etc.), or the use of adjustable aperturesmay be required in order to accommodate the differences among the lungsand associated inspiratory flow rates of young and old, small and large,and various pulmonary disease states. For example, if the aperture isadjustable by the patient (perhaps by having a slotted ring that can berotated), then a method may be provided to read the aperture holesetting and lock that position to avoid inadvertent changes of theaperture hole size, hence the flow measurement. Although pressuresensing is an accurate method for flow measurement, other embodimentsmay use, e.g., hot wires or thermistor types of flow rate measurementmethods which lose heat at a rate proportional to flow rate, movingblades (turbine flow meter technology) or by using a spring-loadedplate, without limitation of example.

For instance, FIGS. 11A-11C illustrate certain exemplary air inlet flowelements of the disclosure. FIGS. 11A-11C also illustrate the positionof pressure sensors, the mouthpiece, and air channels for referencepressure sensing. However, the disclosure is not so limited, and otherconfigurations including those described herein are contemplated aswithin the scope of the disclosure. While not being so limited, the airinlet flow elements of FIGS. 11A-11C are particularly suitable for usewith the in-line droplet delivery devices of FIGS. 1A-1B.

More particularly, FIG. 11A illustrates a cross-section of a partialin-line droplet delivery device with small volume drug ampoules 1000 ofthe disclosure including a mouthpiece cover 1001, a mouthpiece 1002, asmall volume drug ampoule 1003 comprising a reservoir (internal featuresnot shown) 1004 and an ejector mechanism 1005. As illustrated, thedroplet delivery device includes an air inlet flow element 1006 havingan array of holes 1006 a at the air entrance of the mouthpiece 1002.Also shown is a pressure sensor port 1007, which may be used to sense achange in pressure within the mouthpiece. With reference to FIG. 11B, afront view of the device 1000 is illustrated, wherein a second pressuresensor port 1008 is shown to provide for sensing of a reference orambient pressure.

FIG. 11C illustrates a partial exploded view including mouthpiece 1002and inner housing 1011. As shown, mouthpiece 1002 includes air intakeflow element 1006 with an array of holes 1006 a, and pressure sensorport 1007. Further, mouthpiece 1002 may include an ejection port 1114positioned, e.g., on the top surface of the mouthpiece so as to alignwith the ejector mechanism to allow for ejection of the stream ofdroplets into the airflow of the device during use. Other sensor ports1115 may be positioned as desired along the mouthpiece to allow fordesired sensor function, e.g., spray detection. The mouthpiece may alsoinclude positioning baffle 1116 that interfaces with the base unit uponinsertion. Inner housing 1011 includes pressure sensor board 1009 andoutside channel 1010 for facilitating sensing of reference or ambientpressure. The inner housing further includes a first pressure sensingport 1112 to facilitate sensing of pressure changes within the device(e.g., within the mouthpiece or housing), and a second pressure sensingport 1113 to facilitate sensing of reference or ambient pressure.

In this regard, FIG. 12A illustrates differential pressure as a functionof flow rates through exemplary air inlet flow elements similar to thatof FIGS. 11A-11C as a function of number of holes (29 holes, 23 holes,17 holes). Referring to FIG. 12B, the flow rate verses differentialpressure as a function of hole size is shown to have a linerrelationship, when flow rate is plotted as a function of the square rootof differential pressure. The number of holes is held constant at 17holes. These data provide a manner to select a design for an air inletflow element to provide a desired pressure resistance, as well asprovide a model for the relationship between flow rate and differentialpressure, as measured in an exemplary droplet delivery device.

Inspiratory Flow Rate (SLM)=C(SqRt)(Pressure(Pa))

Hole Size (mm) Pressure at Flow at Equation Element # (17 holes) 10 slm(Pa) 1000 Pa Constant (C) 0 1.9 6 149.56 4.73 1 2.4 2.1 169.48 5.36 22.7 1.7 203.16 6.43 3 3 1.3 274.46 8.68

A particular non-limiting exemplary air inlet flow element may 29 holes,each 1.9 mm in diameter. However, the disclosure is not so limited. Forexample, the air inlet flow element may have hole diameters rangingfrom, e.g., 0.1 mm in diameter to diameters equal to the cross sectionaldiameter of the air inlet tube (e.g., 0.5 mm, 1 mm, 1.5 mm, 2 mm, 2.5mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5 mm, 5.5 mm, 6 mm, 6.5 mm, etc.), andnumber of holes may range from 1 to the number of holes, for example, toachieve the desire air flow resistance, e.g., 2, 3, 4, 5, 6, 7, 8, 9,10, 15, 20, 25, 29, 30, 60, 90, 100, 150, etc.

FIGS. 13A-20D illustrate alternative embodiments of air inlet flowelements of the disclosure. FIGS. 13A-20D also illustrate exemplarypositioning of air inlet flow elements within the airflow of a device,within the mouthpiece, as well as the interfacing of a mouthpieceincluding an air inlet flow element to an drug delivery ampoule.

FIG. 13A shows an exemplary drug delivery ampoule with a mouthpieceinterfaced at the airflow exit side of the device. The mouthpieceincludes two airflow entrances on the sides, but no internal air inletflow elements to provide resistance to airflow. FIGS. 13B shows a frontcross-section and 13C shows a side cross-section, with FIG. 13D showingthe same views with exemplary dimensions. FIGS. 14A and 15A showsimilarly configured mouthpieces with two airflow entrances on thesides, but no internal air inlet flow elements to provide resistance toairflow. Again, FIGS. 14B and 15B show a front cross-section and 14C and15C show a side cross-section, with FIGS. 14D and 15D showing the sameviews with exemplary dimensions to illustrate the differences inconfigurations between the embodiments. For instance, the embodiment ofFIG. 13 has openings that are 6.6 mm long and 2 mm high, the embodimentof FIG. 14 has openings that are 7.9 mm long and 2.5 mm high, and theembodiment of FIG. 15 has openings that are 8.1 mm long and 3 mm high.Of course, the disclosure is not limited to these specific dimensions,and varied dimensions and numbers of air inflow openings are envisionsas within the scope of the disclosure.

FIG. 16A shows an exemplary drug delivery ampoule with a mouthpieceinterfaced at the airflow exit side of the device. The mouthpieceincludes two airflow entrances on the exterior sides of the mouthpiece,and two interior baffles with additional airflow entrances to provideresistance and modeling of airflow. FIGS. 16B shows a frontcross-section and 16C shows a side cross-section, with FIG. 16D showingthe same views with exemplary dimensions. FIG. 17A shows a similarlyconfigured mouthpiece that includes two airflow entrances on theexterior sides of the mouthpiece, and two interior baffles withadditional airflow entrances to provide resistance and modeling ofairflow. However, the interior baffles of FIG. 17A are larger (10 mm inheight) than that of FIG. 16A (5 mm in height). FIG. 17B shows a frontcross-section and 17C shows a side cross-section, with FIG. 16D showingthe same views with exemplary dimensions.

FIG. 18A shows an exemplary drug delivery ampoule with a mouthpieceinterfaced at the airflow exit side of the device. The mouthpieceincludes two airflow entrances on the exterior sides of the mouthpiece,and a substantially concentric baffle (two arcs that form a circle withthe top and bottom of the mouthpiece) with two additional airflowentrances to provide resistance and modeling of airflow. FIG. 18B showsa front cross-section and 18C shows a side cross-section, with FIG. 18Dshowing the same views with exemplary dimensions. FIG. 19A shows asimilarly configured mouthpiece with a substantially concentric interiorbaffle, but the interior baffle includes four airflow entrances toprovide resistance and modeling of airflow. FIG. 19B shows a frontcross-section and 19C shows a side cross-section, with FIG. 19D showingthe same views with exemplary dimensions.

FIG. 20A shows an exemplary drug delivery ampoule with a mouthpieceinterfaced at the airflow exit side of the device. The mouthpieceincludes two airflow entrances on the exterior sides of the mouthpiece,and a substantially concentric baffle with two additional airflowentrances to provide resistance and modeling of airflow. In addition,the interior area of the mouthpiece between the concentric baffle andthe wall of the mouthpiece includes an array element positioned abovethe airflow entrances to provide additional resistance and modeling toairflow. The array element is positioned in a parallel arrangement withthe direction of airflow. Again, FIG. 20B shows a front cross-sectionand 19C shows a side cross-section, with FIG. 20D showing the same viewswith exemplary dimensions.

In accordance with the disclosure, it has been found that the presenceof inner air inlet flow elements generally improve spray efficiency forexemplary fluid solutions (deionized water and albuterol solution. Forinstance, as shown in FIG. 21, at 30 SLM, inner air inlet flow elementsincrease spray efficiency from 47% to 66%, and orienting interiorairflow entrances away from ejection streams improves spray efficiencyto 80% or more. The mouthpiece and drug reservoir are a single unit andcan be weighted before ejection (W1), after ejection (W2) and afterdrying (W3) the mouthpiece to measure the percentage of ejected drugthat leaves the mouthpiece for delivery to a user. Sprayefficiency=(W1−W2)/(W1−W3)

In certain aspects of the disclosure, the in-line device with smallvolume drug ampoule may optionally be configured to protect the surfaceof the aperture plate, to minimize evaporation losses, and to minimizecontamination while the device is closed and not in use. However, asmentioned above, in the context of the small volume drug ampoule, aslonger term use and storage of the fluid reservoir on the device is notrequired, in certain embodiments, the small volume ampoule configurationmay not require an aperture plate seal or cover in all embodiments,e.g., to maintain sterility and/or minimize evaporation of thetherapeutic agent fluid.

For instance, as described herein, when the reservoir/ampoule is in theclosed position, the surface of the aperture plate of the ejectormechanism may be closed/sealed against the housing or the mouthpiececover. However, in certain embodiments, when the reservoir/ampouleincludes an O-ring or gasket to facilitate the seal of the surface ofthe aperture plate of the ejector mechanism, the sliding of thereservoir/ampoule between the open and closed position may, in certainaspects, create friction which needs to be overcome by a compressionspring during opening and closing.

In one embodiment, friction between the ampoule O-ring and the devicehousing may be reduced by applying a compressive force between theampoule and the device housing in the last few millimeters as theampoule is closed. Thus, higher friction is limited to the first fewmillimeters during opening, when the compression spring is providing thehighest force; and during the last few millimeters of closing when theampoule door is almost closed and force on the door is easiest for theuser to apply. Force applied as the door is almost closed also createsminimal reaction forces at the door's hinge, improving robustness of thedevice. Applying pressure to the O-ring over a shorter distance alsoreduces wear on the O-ring (or gasket).

Without being limited, in certain embodiments, applying a compressivesealing force during the last few millimeters of ampoule motion to theclosed position can be accomplished by utilizing a ramp on either theampoule or device side of the ampoule track which engages a budge on theopposite face (device for ampoule or ampoule for device) as the ampouleapproaches the closed position. This can also be a pair of ramps whichengage as the ampoule approaches the closed position. In certainaspects, the point(s) of contact between the ampoule and device shouldbe in alignment with the center of pressure of the O-ring to create auniform sealing pressure. Note that to achieve enough compression forgood sealing, the total vertical motion created by the ramp only needsto be in the range of 0.1 mm.

Alternatively to a sealing force generated by a fixed movement of theampoule towards the device, a flexible compressive element can apply adownward force the rises as the ampoule approaches the closed position.By way of non-limiting example, this could be the ramp intersecting aflexible, rubber-like, material or a metallic or plastic spring,including a cantilever (leaf) spring that the ramp encounters as itarrives at the closed position of the ampule.

The compressive force applied to the O-ring does not have to be large,but sufficient for the compliant O-ring to seal against the surfaceroughness of the device surface. In certain embodiments, a morecompliant material will require less compressive force to seal.Similarly, the O-ring can be made from a slippery material such asteflon-coated or teflon-encapsulated material to reduce the slidingfriction of the ampule. Similarly, sealing may be done by a lip seal atthe face.

FIGS. 22A-22C illustrate exemplary embodiments showing a ramp structureon the ampoule lip that presses the ampoule down and compresses theO-ring while in the “closed” position. Note, as illustrated the size ofthe ramp is greatly exaggerated. In one embodiment, the ramp may beabout 0.1 to 0.2 mm high. FIG. 22A shows an end view showing ampule withlips that are engaged in track that is part of body of device. FIG. 22Bshows how an ampoule moves from closed to open position. Mouthpiece anduser to the right. FIG. 21C illustrates a side view of an ampoule intrack with a ramp on a lip to force a aperture plate seal, showing aclosed and open position.

In other embodiments, the surface of the aperture plate may be protectedby the mouthpiece cover. For instance, as shown in FIG. 22D, mouthpiececover 2100 may include aperture plate plug 2102 that is specificallysized and shaped so as to form a mating seal against the surface of theaperture plate 2104 when the cover is closed. In certain embodiments,the aperture plate plug 2102 may have a stepped shape such that the plugforms a seal against the surface of the housing around the apertureplate without putting direct pressure on the surface of the apertureplate.

In certain embodiments, as illustrated herein, the reservoir/cartridgemodule may include components that may carry information read by thehousing electronics including key parameters such as ejector mechanismfunctionality, drug identification, and information pertaining topatient dosing intervals. Some information may be added to the module atthe factory, and some may be added at the pharmacy. In certainembodiments, information placed by the factory may be protected frommodification by the pharmacy. The module information may be carried as aprinted barcode or physical barcode encoded into the module geometry(such as light transmitting holes on a flange which are read by sensorson the housing). Information may also be carried by a programmable ornon-programmable microchip on the module which communicates to theelectronics in the housing.

By way of example, module programming at the factory or pharmacy mayinclude a drug code which may be read by the device, communicated viaBluetooth to an associated user smartphone and then verified as correctfor the user. In the event a user inserts an incorrect, generic,damaged, etc., module into the device, the smartphone might be promptedto lock out operation of the device, thus providing a measure of usersafety and security not possible with passive inhaler devices. In otherembodiments, the device electronics can restrict use to a limited timeperiod (perhaps a day, or weeks or months) to avoid issues related todrug aging or build-up of contamination or particulates within thedevice housing.

The in-line droplet delivery device may further include various sensorsand detectors to facilitate device activation, spray verification,patient compliance, diagnostic mechanisms, or as part of a largernetwork for data storage, big data analytics and for interacting andinterconnected devices used for subject care and treatment, as describedfurther herein. Further, the housing may include an LED assembly on asurface thereof to indicate various status notifications, e.g.,ON/READY, ERROR, etc.

The airflow exit of the housing of the droplet delivery device throughwhich the ejected plume of droplets exit as they are inhaled into asubject's airways, may be configured and have, without limitation, across sectional shape of a circle, oval, rectangular, hexagonal or othershape, while the shape of the length of the tube, again withoutlimitation, may be straight, curved or have a Venturi-type shape.

In another embodiment (not shown), a mini fan or centrifugal blower maybe located at the air inlet side of the laminar flow element orinternally of the housing within the airsteam. The mini fan generallymay provide additional airflow and pressure to the output of the plume.For patients with low pulmonary output, this additional airplume mayensure that the plume of droplets is pushed through the device into thepatient's airway. In certain implementations, this additional source ofairflow ensures that the plume exit port is swept clean of the dropletsand also provides mechanism for spreading the particle plume into anairflow which creates greater separation between droplets. The airflowprovided by the mini fan may also act as a carrier gas, ensuringadequate dose dilution and delivery.

In other embodiments, the internal pressure resistance of the in-linedroplet delivery device may be customized to an individual user or usergroup by modifying the mouthpiece tube design to include variousconfigurations of air aperture grids or openings, thereby increasing ordecreasing resistance to airflow through the device as the user inhales.For instance, different air entrance aperture sizes and numbers may beused to achieve different resistance values, and thereby differentinternal device pressure values. This feature provides a mechanism toeasily and quickly adapt and customize the airway resistance of theparticle delivery device to the individual patient's state of health orcondition.

In another aspect of the disclosure, in certain embodiments, the in-linedroplet delivery devices provide for various automation, monitoring anddiagnostic functions. By way of example, as described above, deviceactuation may be provided by way of automatic subject breath actuation.Further, in certain embodiments, the device may provide automatic sprayverification, to ensure that the device has generated the properparticle generation and provided to proper dosing to the subject. Inthis regard, the particle delivery device may be provided with one ormore sensors to facilitate such functionality.

For instance, an airflow sensor located in the mouthpiece may measureinspiratory and expiratory flow rates. This sensor is placed so that itdoes not interfere with drug delivery or become a site for collection ofresidue or promote bacterial growth or contamination. A differential (orgage) pressure sensor downplume of a flow restrictor (e.g., air inletflow element) measures airflow based upon the pressure differentialbetween the inside of the mouthpiece relative to the outside airpressure. During inhalation (inspiratory flow) the mouthpiece pressurewill be lower than the ambient pressure and during exhalation(expiratory flow) the mouthpiece pressure will be greater than theambient pressure. The magnitude of the pressure differential during aninspiratory cycle is a measure of the magnitude of airflow and airwayresistance at the air inlet end of the delivery tube.

Again, a Bluetooth communication module or similar wirelesscommunication module may be provided in order to link the dropletdelivery device to a smartphone or other similar smart devices (notshown). Bluetooth connectivity facilitates implementation of varioussoftware or App's which may provide and facilitate patient training onthe use of the device. A major obstacle to effective inhaler drugtherapy has been either poor patient adherence to prescribed aerosoltherapy or errors in the use of an inhaler device. By providing a realtime display on the smartphone screen of a plot of the patient'sinspiratory cycle, (flow rate versus time) and total volume, the patientmay be challenged to reach a goal of total inspiratory volume that waspreviously established and recorded on the smartphone during a trainingsession in a doctor's office. Bluetooth connectivity further facilitatespatient adherence to prescribed drug therapy and promotes compliance byproviding a means of storing and archiving compliance information, ordiagnostic data (either on the smartphone or cloud or other largenetwork of data storage) that may be used for patient care andtreatment.

More specifically, in certain embodiments, the droplet delivery devicemay provide automatic spray verification via LED and photodetectormechanisms. For instance, an infra-red transmitter (e.g., IR LED, or UVLED <280 nm LED), and infra-red or UV (UV with <280 nm cutoff)photodetector may be mounted along the droplet ejection side of thedevice to transmit an infra-red or UV beam or pulse, which detects theplume of droplets and thereby may be used for spray detection andverification. The IR or UV signal interacts with the aerosol plume andcan be used to verify that a plume of droplets has been ejected as wellas provide a measure of the corresponding ejected dose of medicament.Examples include but not limited to, infrared 850 nm emitters withnarrow viewing angles of either, 8, 10 and 12-degrees, (MTE2087 series)or 275 nm UV LED with a GaN photodetector for aerosol plume verificationin the solar blind region of the spectra. Alternatively in someapplications, the sub 280 nm LEDs (e.g. 260 nm LEDs) can be used todisinfect the spacer tube.

By way of example, the concentration of a medicament in the ejectedfluid may be made, according to Beer's Law Equation (Absorbance=e L c),where, e is the molar absorptivity coefficient (or molar extinctioncoefficient) which is a constant that is associated with a specificcompound or formulation, L is the path length or distance between LEDemitter and photodetector, and c is the concentration of the solution.This implementation provides a measure of drug concentration and can beused for verification and a means and way to monitoring patientcompliance as well as to detect the successful delivery of medication.

In another embodiment, spray verification and dose verification can bemonitored by measuring the transmission of 850 nM to 950 nM light acrossthe spray in a region where the droplets are not variably diluted withdifferent inhalation flow rates. The average and alternating signalsfrom the detector may be measured to calibrate and confirm the opticalpath (average signal) and detect the spray (alternating signal). Inpractice, the alternating signal can be measured by a 100 Hz low-passfilter between the detector and analog converter, sampling the signal100 to 500 times a second, calculating the average and the range(maximum minus minimum) over 100 mS periods, and comparing these valuesto preset values to confirm proper operation and whether there was sprayor not.

This method has the strong advantages of: low power consumption (lessthan 1 ma to the emitter); unaffected by stray light (visible lightblocking on the detector); relatively resistant to digital noise or the100 kHz piezo drive by the 100 Hz low-pass filter; the average signallevel can be used to adjust the optical path for attenuation caused bydrug deposits on the LED or detector; and simple hardware with apositive signal that is robustly measured.

This system also allows simple regulation of the optical signal strengthby increasing power to the emitter should the average signal leveldecrease. Practically, this means using pulse width modulation ofemitter current to regulate average emitter power. The pulses should beat a high rate, e.g., 100 kHz, so that this noise can be removed by the100 Hz low pass filter. Nominal operation might use a 10% duty cycle of10 mA to achieve and average current of 1 mA. This system would have theability to increase the average current to 10 mA and correct for up to afactor of 10 attenuation by drug deposits.

In operation with the 950 nM emitter and detector having angles of +−20degrees and spaced 10 mm apart. With 0.5 mA emitter power, a 10Kcollector resistor and 100 Hz low-pass filter, the average signal outputis 2 volts and the peak to peak value of the alternating component is 4mV without spray and 40 mV during spray. Without intending to belimited, in practice, there may be a transient large peak to peak valuewhen the spray begins and ends as the bulk attenuation causes a largeshift. The resistor sizing here is for continuous running of the emitterand not PWM.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically, and individually, indicated to beincorporated by reference.

While the invention has been described with reference to exemplaryembodiments, it will be understood by those skilled in the art thatvarious changes may be made and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particular situationor material to the teachings without departing from the essential scopethereof. Therefore, it is intended that the invention not be limited tothe particular embodiment disclosed as the best mode contemplated forcarrying out this invention, but that the invention will include allembodiments falling within the scope of the appended claims.

What is claimed:
 1. An electronically actuated droplet delivery devicefor delivering a fluid as an ejected stream of droplets to the pulmonarysystem of a subject, the device comprising: a housing; a mouthpiecepositioned at an airflow exit of the device; an air inlet flow elementpositioned in the airflow at an airflow entrance of the device; a smallvolume drug ampoule disposed in or in fluid communication with thehousing including a drug reservoir for receiving a small volume offluid; an electronically actuated ejector mechanism in fluidcommunication with the reservoir and configured to generate the ejectedstream of droplets; at least one differential pressure sensor positionedwithin the housing, the at least one differential pressure sensorconfigured to activate the ejector mechanism upon sensing apre-determined pressure change within the mouthpiece to thereby generatethe ejected stream of droplets; the ejector mechanism comprising apiezoelectric actuator and an aperture plate, the aperture plate havinga plurality of openings formed through its thickness and thepiezoelectric actuator operable to oscillate the aperture plate at afrequency to thereby generate the ejected stream of droplets; whereinthe housing, air inlet flow element, and mouthpiece are configured tofacilitate non-turbulent airflow across an exit side of the apertureplate and to provide sufficient airflow through the housing during use;and wherein the ejector mechanism is configured to generate the ejectedstream of droplets wherein at least about 50% of the droplets have anaverage ejected droplet diameter of less than about 6 microns, such thatat least about 50% of the mass of the ejected stream of droplets isdelivered in a respirable range to the pulmonary system of the subjectduring use.
 2. The droplet delivery device of claim 1, wherein the smallvolume drug ampoule comprises a reservoir including an internal flexiblemembrane separating two internal volumes, a first background pressurefluid volume and a second drug volume received by the drug reservoir. 3.The droplet delivery device of claim 1, wherein the housing and ejectormechanism are oriented such that the exit side of the aperture plate isperpendicular to the direction of airflow and the stream of droplets isejected in parallel to the direction of airflow.
 4. The droplet deliverydevice of claim 1, wherein the housing and ejector mechanism areoriented such that the exit side of the aperture plate is parallel tothe direction of airflow and the stream of droplets is ejectedsubstantially perpendicularly to the direction of airflow such that theejected stream of droplets is directed through the housing at anapproximate 90 degree change of trajectory prior to expulsion from thehousing.
 5. The droplet delivery device of claim 1, wherein the airinlet flow element is positioned within the mouthpiece.
 6. The dropletdelivery device of claim 5, wherein the air inlet flow element ispositioned behind the exit side of the aperture plate along thedirection of airflow.
 7. The droplet delivery device of claim 5, whereinthe air inlet flow element is positioned in-line or in front of the exitside of the aperture plate along the direction of airflow.
 8. Thedroplet delivery device of claim 1, wherein the air inlet flow elementcomprises one or more openings formed there through and configured toincrease or decrease internal pressure resistance within the dropletdelivery device during use.
 9. The droplet delivery device of claim 8,wherein the air inlet flow element comprises an array of one or moreopenings.
 10. The droplet delivery device of claim 8, wherein the airinlet flow element comprises one or more baffles.
 11. The dropletdelivery device of claim 10, wherein the one or more baffles compriseone or more airflow openings.
 12. The droplet delivery device of claim1, wherein the aperture plate comprises a domed shape.
 13. The dropletdelivery device of claim 1, wherein the aperture plate is composed of amaterial selected from the group consisting of poly ether ether ketone(PEEK), polyimide, polyetherimide, polyvinylidine fluoride (PVDF),ultra-high molecular weight polyethylene (UHMWPE), nickel,nickel-cobalt, nickel-palladium, pallaidium, platinum, metal alloysthereof, and combinations thereof.
 14. The droplet delivery device ofclaim 1, wherein one or more of the plurality of openings have differentcross-sectional shapes or diameters to thereby provide ejected dropletshaving different average ejected droplet diameters.
 15. The dropletdelivery device of claim 1, wherein the mouthpiece is removably coupledwith the device.
 16. The droplet delivery device of claim 1, wherein thereservoir is removably coupled with the housing.
 17. The dropletdelivery device of claim 1, wherein the reservoir is coupled to theejector mechanism to form a combination reservoir/ejector mechanismmodule, and the combination reservoir/ejector mechanism module isremovably coupled with the housing.
 18. The droplet delivery device ofclaim 1, further comprising a wireless communication module.
 19. Thedroplet delivery device of claim 1, wherein the device further comprisesone or more sensors selected from an infra-red transmitter, aphotodetector, an additional pressure sensor, and combinations thereof.20. A method for delivering a therapeutic agent as an ejected stream ofdroplets in a respirable range to the pulmonary system of a subject forthe treatment of a pulmonary disease, disorder or condition, the methodcomprising: (a) generating an ejected stream of droplets via apiezoelectric actuated droplet delivery device of claim 1, wherein atleast about 50% of the ejected stream of droplets have an averageejected droplet diameter of less than about 6 μm; and (b) delivering theejected stream of droplets to the pulmonary system of the subject suchthat at least about 50% of the mass of the ejected stream of droplets isdelivered in a respirable range to the pulmonary system of a subjectduring use to thereby treat the pulmonary disease, disorder orcondition.